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Roberto Kolter
Annual Review of Microbiology
The History of Microbiology—
A Personal Interpretation
Roberto Kolter
Department of Microbiology, Harvard Medical School, Boston, Massachusetts 02115, USA;
Annu. Rev. Microbiol. 2021.75:1-17. Downloaded from www.annualreviews.org
email: roberto_kolter@hms.harvard.edu
Annu. Rev. Microbiol. 2021. 75:1–17 Keywords

First published as a Review in Advance on
microbiology, ecology, evolution, genetics, biochemistry
May 11, 2021
The Annual Review of Microbiology is online at Abstract

micro.annualreviews.org
Microbiology began as a unified science using the principles of chemistry to
https://doi.org/10.1146/annurev-micro-033020-
understand living systems. The unified view quickly split into the subdisci-
020648
plines of medical microbiology, molecular biology, and environmental mi-
Copyright © 2021 by Annual Reviews.
crobiology. The advent of a universal phylogeny and culture-independent
All rights reserved
approaches has helped tear down the boundaries separating the subdisci-
plines. The vision for the future is that the study of the fundamental roles
of microbes in ecology and evolution will lead to an integrated biology with
no boundary between microbiology and macrobiology.
1
Contents
PROLOGUE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
MICROBIOLOGY COMES OF AGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
THE FIRST SCHISM—THE BIRTH OF MEDICAL MICROBIOLOGY . . . . . . . . 3
THE SECOND SCHISM—THE BIRTH OF MOLECULAR BIOLOGY . . . . . . . . . 4
WHERE ART THOU, GENERAL MICROBIOLOGY? . . . . . . . . . . . . . . . . . . . . . . . . . . 5
THE GOLDEN AGE (AND THE DARK SIDE) OF ANTIBIOTICS . . . . . . . . . . . . . 6
MOLECULAR BIOLOGY REVEALS THE INNER WORKINGS
OF THE (E. COLI) CELL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
BACK FROM THE ASHES, MICROBIAL ECOLOGY RISES AGAIN . . . . . . . . . . . . 9
REUNIFICATION: IT’S ALL ENVIRONMENTAL MICROBIOLOGY . . . . . . . . . . 11

EPILOGUE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
PROLOGUE
As part of the celebration of 75 years of this Annual Reviews journal, the Editorial Committee
invited me to contribute a retrospective reviewing the last 75 years of microbiology. I accepted
the invitation with a strange mixture of alacrity and hesitation. I very much love history, but
I am by no stretch of the imagination a historian. So, I chose to write this personal interpretation of
what I perceive as the most critical developments in the history of microbiology. As a consequence,
there are many important advances that I do not cover, and for that I ask exculpation. Restriction
enzymes, thermostable DNA polymerases, and of course CRISPR all come to mind as microbial
discoveries that led to technological revolutions. Those I do not mention. My aim is to describe
how thinking about microbes evolved as separate disciplines through most of the twentieth
century and how these boundaries have begun to crumble in recent decades. While my emphasis
is on developments since the mid-1940s, I first present the early history of microbiology as
backdrop.
I would be remiss not to mention that I find myself writing this article in the midst of the
coronavirus disease 2019 (COVID-19) pandemic. In less than a year, two revolutionary mRNA
vaccines were approved, speaking volumes about the contribution of microbial sciences to human
health. This is not the place, nor am I the appropriate author, to cover any of the many aspects
of the pandemic. Nonetheless, I am convinced that the course of the history of microbiology will
be dramatically altered. Never before in my lifetime have I witnessed so much general interest
in science. We should see this as a special opportunity to increase our efforts to understand the
workings of the microbial world and to disseminate that knowledge.
MICROBIOLOGY COMES OF AGE

When viewed through the lens of today’s lightning-fast developments in science, microbiol-
ogy took an eternity to come into its own. Two hundred years elapsed between Antonie van
Leeuwenhoek’s (1) descriptions of dierken—little animals or animalcules—and Louis Pasteur’s (66)
introduction of the term microbe, originally coined by the surgeon Charles Sédillot, into the liter-
ature in 1878. The cumulative knowledge that gave birth to microbiology, most of it gained in the
second half of the nineteenth century, came from applying multidisciplinary approaches to inves-
tigate the diverse microbial activities on the planet. The result was a unified view of microbiology.
2 Kolter
This unified view is evident when we analyze the work of three of the most influential early
microbiologists: Pasteur, Martinus Beijerinck, and Sergei Winogradsky. All three trained in chem-
istry, which led them to investigate the underlying chemical mechanisms at work in different mi-
crobial systems. From this vantage they were instrumental in developing our early understanding
of the many roles played by microbes in phenomena ranging from respiration and fermentation
to the biogeochemical cycles of Earth. In addition, all three recognized the complex interplay
of microbes with their environments in the settings they investigated (16, 26, 27). They were all
pioneers in microbial ecology.
The ecological perspectives that guided these three led them to have remarkably broad inter-
ests. Pasteur investigated wine fermentation and its maladies, observed how environmental condi-
tions altered the outcome of silkworm diseases, and developed vaccinations for rabies and anthrax,
to mention but a few of his many accomplishments. Beijerinck was equally at home studying the
mutualism of nitrogen fixation by bacteria in root nodules or the parasitism of plant infection
by tobacco mosaic virus. Winogradsky explored nitrification, discovered chemosynthesis, and in-
vented the columns that bear his name, where the interconnectedness of the diverse metabolic
capacities of microbes becomes readily apparent. For all three, such wide ranges of interests came
naturally, for they all had a unified worldview of microbiology and recognized the need to study
microbes through multidisciplinary approaches. This broad scientific thinking is elegantly sum-
marized in Pasteur’s (66) opening sentence of his germ theory essay from 1878: “Les sciences gagnent
toutes à se pretêr un mutuel appui” (The sciences all benefit from mutual support).
THE FIRST SCHISM—THE BIRTH OF MEDICAL MICROBIOLOGY

The unified worldview implicit in the work of Pasteur, Beijerinck, and Winogradsky, where micro-
bial pathogenesis was very much a part of environmental microbiology, would not last long. The
major driver for the coming change in worldview was the work of Robert Koch. A contemporary
of Pasteur’s and usually at odds with him (80), Koch was trained as a physician and his interests
were very much focused on infectious diseases (10). The powerful appeal of Koch’s unequivocal
demonstration that bacteria were causative agents of important infectious diseases put medical as-
pects of microbiology at center stage. It is difficult to overstate the impact that Koch’s postulates
and his development of techniques to obtain pure cultures had on microbiology (10). Knowing
that bacteria were causative agents of infectious diseases, long the major cause of human mortality,
meant that if you could kill the bacteria responsible, you could cure the disease. By the turn of the
twentieth century, microbiology was largely focused on efforts to identify the microbes behind
human infectious diseases. The horrendous death toll resulting from the influenza pandemic of
1918 only accelerated those efforts (6). Because identification of the influenza virus would not
happen until the 1930s, before which the culprit was thought to be a bacterium, many pathogenic
bacteria were identified and intensively studied in the years following the pandemic (81). In that
context, studies on the beneficial aspects of microbes were largely cast aside.
Alongside the efforts to identify pathogenic microbes, many microbiologists turned their at-
tention to the discovery of compounds capable of specifically killing those microbes, resulting in
the most dramatic revolution in the history of human medicine of the twentieth century. Early
efforts by Sahachiro Hata and Paul Ehrlich resulted in the first organic antimicrobial, the rather
toxic arsenical arsphenamine (Salvarsan), used to treat syphilis as early as 1910 (83). Protracted
efforts to use dyes as antibacterial magic bullets led to the somewhat serendipitous discovery of
the sulfa drugs, starting with sulfamidochrysoidine (Prontosil), that went into clinical use during
the 1930s (31). But without a doubt, the most influential of the early antimicrobials was penicillin
(14). From Alexander Fleming’s accidental discovery of penicillin in 1928 to its purification and
www.annualreviews.org • The History of Microbiology 3

effective use by injection in 1942 through the pioneering work of Howard Florey, Ernst Chain,
Margaret Jennings, and others at Oxford University, the development of this antibiotic remains
one of humanity’s greatest accomplishments.
The discovery of a clinically useful microbial product that killed other microbes had a lasting
effect on the history of microbiology, of medicine, and of the entire pharmaceutical industry (14).
There was an enormous and very successful rush to discover additional antibiotics. The clinical
success of antibiotics led to their increased production. This was initially aided by the world war
mentality of the early 1940s. Because penicillin was seen as the miracle drug of the war, its pro-
duction increased dramatically in a very short time. The worldwide stock was a few milligrams in
1941, and by 1945 nearly 4,000 kg were being produced per month (14). Once such a tonnage of
antibiotics was available for sale, it had to be sold and widely used. Because of the schism away from
environmental microbiology, medical microbiology paid little attention to the ecological conse-
quences of producing and using such vast amounts of antimicrobials. There was precious little
conversation between those interested in the means to eradicate pathogenic bacteria and those
interested in microbial ecology.
THE SECOND SCHISM—THE BIRTH OF MOLECULAR BIOLOGY

Research on a bacterial pathogen provided a key finding that served as a founding pillar for the
development of molecular biology. In 1928, Frederick Griffith (34) reported that avirulent strains
of the pneumococcus, now known as Streptococcus pneumoniae, could be transformed to become
stably virulent strains when coinjected with heat-killed virulent strains into mice. Oswald Avery,
Colin MacLeod, and Maclyn McCarty, still coming from the perspective of wanting to under-
stand virulence, set out to purify the so-called transforming principle. Their extensive purification
and characterization—the fundamental approaches of biochemistry—led them to the surprising
conclusion, published in 1944 (2, p. 156), that “the evidence presented supports the belief that
a nucleic acid of the desoxyribose type is the fundamental unit of the transforming principle of
Pneumococcus Type III.” In today’s parlance, the evidence pointed to DNA as the genetic mate-
rial. Perhaps because this work’s conclusion was so unexpected—genes were widely believed to be
made of protein—and perhaps because the conclusion was so mildly stated, the work was received
with a mixture of enthusiasm by some and disbelief by others. As a consequence, the results did
not receive the widespread and immediate recognition one might have expected (18). It is partic-
ularly surprising that a key player in the early days of molecular genetics, Max Delbrück, did not
immediately begin to study the role of DNA in genetics upon learning of Avery et al.’s results.
This was likely due, at least in part, to Delbrück’s expressed dislike of biochemistry (74).
During the years that Avery and colleagues were purifying the transforming principle,
Delbrück became the driving force that led to the birth of microbial genetics. Initially trained
as a physicist in Germany, Delbrück had become interested in genes and mutations in the early
1930s (77). Delbrück left Germany for Caltech in 1938, before the onset of World War II, to
work on Drosophila genetics with Thomas Morgan. To a physicist interested in finding a sim-
ple system in which to study how life begets life, the fruit fly proved way too complicated. He
turned instead to microbiology. He had already developed an outsider’s interest in viruses while in
Germany, so it was a perfect match when he met Emory Ellis, who was studying bacteriophages
that killed Escherichia coli in hopes of understanding cancer. Ellis’s choice of E. coli appears to have
been serendipitous; the bacterium grew fast, it was not fastidious, and, importantly, it was avail-
able from one of Morgan’s students (76). For a physicist interested in unraveling the mysteries of
biological replication, a system where an individual gave rise to a progeny of hundreds in a matter
of minutes had to have been a dream come true.
4 Kolter
By the early 1940s, Delbrück had formed collaborations with two other phage workers,
Salvador Luria and Alfred Hershey. Together they started the famed Phage Group (21). The
1943 Luria & Delbrück (52) paper on the random and spontaneous nature of phage-resistant mu-
tants marks the beginning of microbial genetics. In 1944, Delbrück put forth the Phage Treaty,
in decreeing that all phage workers should focus their work on the T phages of E. coli so that
all experiments could be compared (21). To further ensure standardization of phage experiments,
Delbrück started the summer Phage Course at Cold Spring Harbor, New York, in 1945 (20). This
very focused phage work proved extremely productive and led to many important insights into
the workings of living systems.
By the end of World War II, the stage was set for the work that over the next three decades
would lead to a deep understanding of genes and their functions. Molecular biology was born.
The key tactic in molecular biology was to mix genetics and biochemistry, the perfect meld of
the separate approaches to study genes used by the Phage Group on the one hand and Avery and
colleagues on the other. The strong allure of working on the simple and elegant system of E. coli
and its phages to understand the molecular basis of gene function meant that studies on microbial
diversity, ecology, and evolution, took a back seat for a few years.
WHERE ART THOU, GENERAL MICROBIOLOGY?

Taking a back seat did not mean, by any stretch of the imagination, a disappearance. The Delft
School of Microbiology, which started with Beijerinck, provided the starting point for much of the
general microbiology that was done during the first half of the twentieth century. When Beijerinck
retired, in 1921, his position was filled by Albert Jan Kluyver, also a chemist. Kluyver continued the
tradition of working with many different microbes. Underlying their metabolic diversity, Kluyver
discovered that the reactions of central metabolism were always the same. To emphasize this unity
in biochemistry, he coined the phrase “from elephant to butyric acid bacterium—it is all the same”
(48, p. 20; 70). This unity in central metabolism served as a springboard from which to determine
and compare the metabolic capacities of different microbes. The legacy of Kluyver’s work thus
also includes the vast knowledge we have of microbial metabolic pathways, a knowledge about
which many microbiologists are, sadly, largely ignorant to this day (25).
Kluyver trained many individuals at Delft but none more notable than Cornelis van Niel (4).
After spending seven years with Kluyver, Van Niel moved to the Hopkins Marine Station in the
Monterey Peninsula in California in 1928. While Van Niel’s major contributions surround the
topic of bacterial photosynthesis, he was very much a generalist, investigating innumerable areas
of microbial physiology. Importantly, his interests in the diversity he observed among microbes
generated in him a deep interest in understanding microbial evolution. A necessary step in this was
to establish a bacterial phylogeny, a task he stuck with but was not able to complete. His passion for
microbiology, along with what he saw as a great ignorance in the United States of the contributions
of Beijerinck and Kluyver, prompted Van Niel to organize a general microbiology course, starting
in 1930. The course became legendary, every summer attracting a few individuals—among them
Roger Stanier, in 1938—who would go on to keep the tradition of general microbiology alive
for decades (82). Because of its emphasis on the metabolic diversity of the microbial world, Van
Niel’s course stands in stark contrast to Delbrück’s Phage Course. Both turned out to be highly
influential in the history of microbiology, but they could not have been more different.
Thus stood microbiology at the midpoint of the twentieth century. What had started as
a unified discipline had separated into the subdisciplines of medical microbiology, molecular
microbiology, and environmental microbiology. Sadly, they had little cross communication, a

separation that would remain for at least 25 years. In some ways, this separation can still be felt
today. But in many other ways, a reunification that started nearly 50 years ago has been steadily
growing.
THE GOLDEN AGE (AND THE DARK SIDE) OF ANTIBIOTICS

The revolution that was triggered by the development of penicillin was greatly amplified by the
development of many other antibiotics. The discovery of streptomycin from Streptomyces griseus,
by Albert Schatz and Selman Waksman in 1943 (85), had two important consequences. First, it
generated a worldwide explosion of very productive searches for new natural product antibiotics
made by soil bacteria, many of them members of the genus Streptomyces. For at least 20 years these
searches yielded many new antimicrobials and, importantly, new structural classes of clinically
useful antibiotics. This period has rightly been named the golden era of antibiotic discovery. Along
with the discovery came the rapid growth of the pharmaceutical industry, as these new compounds
went through the required phases to take them from discovery to drug development to widespread
clinical applications. Second, streptomycin was shown effective in the treatment of pulmonary
tuberculosis through what is recognized to have been the first successful randomized clinical trial
(59). While the trial was not double-blind and placebo controlled, it helped define how the efficacy
of newly developed drugs would be tested going forward.
In part because medical microbiology had lost contact with environmental microbiology, the
ecological consequences of widespread antibiotic use were not taken seriously by the pharmaceuti-
cal industry and the medical profession. Since most of the successful antibiotics used have a broad
spectrum of activity, once administered they wreak havoc on the microbial communities of the
patient (50). This amounts to a scorched-earth attack on microbes. Not surprisingly, soon after
new antibiotics are introduced, antibiotic-resistant strains appear (17). Despite claims to the con-
trary, it is a reality that if an antibiotic is broadly used resistance will be observed. Regardless of the
knowledge that antibiotic resistance eventually renders antibiotics useless, antibiotic production
and use have increased continually since the early days of the antibiotic era to this day (15).
To make matters worse, antibiotics were not only used, they were quickly abused. In 1945,
scientists at Lederle Laboratories (American Cyanamid) characterized a bacterium that produced
gold-colored colonies. They named it Streptomyces aureofaciens (gold maker), perhaps hoping it
would bring in real gold. From S. aureofaciens they obtained the first tetracycline, aureomycin (47).
At the same time at Lederle, Thomas Jukes and Robert Stokstad assayed the waste product from
aureomycin production to determine whether it contained vitamin B12 , using recovery of starved
chickens as their assay. Amazingly, when chickens were fed the waste product (which contained
trace amounts of aureomycin) their growth was greatly accelerated. In 1950, they reported that
the inexpensive wonder drug aureomycin added in very small amounts to animal feed increased
the growth of farmed animals by 50% (51). Soon thereafter, the practice of using antibiotics as
growth promoters became widespread and grew exponentially (15). Unfortunately, despite many
efforts to end it, the practice continues to grow (94).
The overuse and abuse of antibiotics constitute the very dark side of these astonishing drugs.
Precise numbers on the amounts of antibiotics produced worldwide are hard to come by, as com-
panies need not make those numbers public. Current estimates suggest that 100,000 tons are pro-
duced per year, with more than half used for growth promotion in animal husbandry (15). Since
the majority of the antibiotics pass through human or animal, it is no surprise that they end up
in soil and water and become what amounts to an ecological catastrophe whose global effects we
are only beginning to appreciate (67). What is clear is that the spread of antibiotic resistance has
reached critical levels (15). So much so that many are already forecasting a post-antibiotic era (68).
6 Kolter
MOLECULAR BIOLOGY REVEALS THE INNER WORKINGS
OF THE (E. COLI) CELL
A quick look at the progress made in molecular biology from 1947 to 1976 leaves one in absolute
wonderment. Science went from a state of uncertainty as to the nature of the gene to a rather com-
plete understanding of the molecular underpinnings of replication, transcription, translation and
the basics of how these processes are regulated. Most of the advances were the result of a coming
together of bacterial genetics (the legacy of Delbrück and the Phage Group) and biochemistry
(exemplified by the purify-and-characterize approach of Avery), with critical contributions from
biophysics. At the center of it all was E. coli and its phages.
The resistance of many scientists to accept Avery’s results slowly began to erode. Many budding
biophysicists were attracted to the idea of the genes being DNA, not least because William Astbury,
who had done early X-ray crystallographic analyses on DNA in the 1930s, had been positively
impressed (35). By 1950 even several members of the Phage Group began to toy with the idea
that phage injected only their DNA into the cell to generate new phage (18). In 1952, Hershey
and Chase reported on an experiment designed to test this idea by differentially labeling phage
proteins with 35 S and DNA with 32 P. The results of the now classic Hershey-Chase experiment
suggested that the DNA entered the cell while the protein stayed outside (37). The results quickly
gained acceptance as evidence that DNA was the substance of genes.
By the time the Hershey-Chase paper was published in 1952, two groups in the United King-
dom were hard at work on the structure of DNA, one at King’s College in London and one at Cam-
bridge University. The events that transpired between 1951 and early 1953, when the structure of
the double helix was published, are the stuff of legends and have been written about and analyzed in
extensive detail (46, 53, 86). They remain an excellent case study in the conduct of science and are
worth studying by scientists of all ages. Head of the Medical Research Council Biophysics Unit at
King’s College, John Randall exercised poor management form by miscommunicating with Ros-
alind Franklin and Maurice Wilkins as to how and by whom X-ray crystallographic studies were to
be conducted, creating a terrible working environment (53). Despite this bad situation, Franklin
obtained superb diffraction images of DNA fibers (32). One of them, the now famous Photo 51,
was given to Francis Crick and James Watson, at Cambridge University, without Franklin’s knowl-
edge. The photograph, along with a site visit report that contained many of Franklin’s calculations
(also obtained surreptitiously), allowed Crick and Watson to put the finishing touches on their
model for the structure of DNA (87). Franklin died in 1958 without knowledge of how her results
had been used in building the model. What was perhaps the most important discovery in the life
sciences of the twentieth century is thus tainted, though by no means diminished in its importance.
In hindsight, it is easy to imagine that a single look at DNA structure would reveal the mech-
anisms of DNA replication and protein synthesis. Nothing could be further from the truth. But
the structure certainly gave all the incentive necessary to tackle those problems with all the tools
available. In less than a decade, the general mechanisms of replication and protein synthesis were
worked out.
“It has not escaped our notice that the specific pairing we have postulated suggests a possible
copying mechanism for the genetic material” (87, p. 737). That is probably the best-known single
sentence in the double-helix paper. The proof that the mechanism of DNA replication is indeed
semiconservative stands as one of the most elegant experiments of that era (58). Matthew Mesel-
son, a graduate student, and Frank Stahl, a postdoc, both at Caltech, showed this by labeling the
DNA with a heavy, stable isotope of nitrogen by growing E. coli with 15 NH4 Cl. Subsequently, they
shifted the cells to a medium containing the light isotope 14 N. They separated DNAs of different
densities using equilibrium density gradient centrifugation. Both DNA strands from the starting

culture were heavy. After one cycle of replication, all the DNA had shifted to an intermediate den-
sity, consistent with each new strand having been made with the light isotope. Importantly, after
the second round of replication, half of the DNA had both strands made from the light isotope
while the other half of the DNA was still of intermediate density. These results were most consis-
tent with a semiconservative mode of replication. Their results, published in 1958, were dubbed
“the most beautiful experiment in biology” (40). In a wonderful testament of the lasting friendship
of Meselson and Stahl, their recollections were recorded in a 2020 interview that is a must-watch
for all (57).
After the proof of the semiconservative nature of the replication process came the long quest
to identify the enzymes involved. Two decades went by before the subunits of the replicase were
all identified and then placed in the context of an even more complex replisome (3). A key take-
home message of how this was accomplished is that the most productive approaches made use
of conditional mutants that were temperature sensitive for replication (38). Cell-free extracts of
these mutants were used to develop in vitro replication systems with single-stranded phage DNA
as a template. These systems could be complemented by extracts from wild-type cells as a way to
purify the missing component. In the following decades, such powerful melding of genetics and
biochemistry proved extremely useful in characterizations of other basic cellular processes, e.g.,
building of the cell envelope, protein secretion, and protein turnover.
Understanding how the information contained in DNA is processed to yield proteins be-
came a critical question soon after the DNA structure was proposed. In 1954, the cosmologist
George Gamow proposed a process whereby protein synthesis occurred on the surface of the
DNA through a key-and-lock mechanism where each amino acid would act as a key that specifi-
cally fit into one of the 20 holes or locks possible from the base pairs in the double helix (33). Crick
dismissed the idea based on prior evidence from eukaryotic cells that protein synthesis occurred
in the cytoplasm while the DNA was in the nucleus. Still, Gamow’s concept that the sequence of
bases in the DNA contained the protein sequence information was readily accepted.
Most of the basics of how DNA is transcribed into mRNA by RNA polymerase and how the
mRNA is translated into protein at the ribosome, plus deciphering of the genetic code, were pub-
lished in 1961, a remarkable year for molecular biology. Ribosomes were discovered and described
as the sites of protein synthesis in eukaryotic cells in 1955 (64), and the existence of tRNA was re-
ported in 1958 (39). But by the end of 1960, almost no more details had been published. Then, in a
short spurt of advances, all the pieces of the puzzle fell into place. Based on the genetic analyses of
phage mutants, Crick along with Leslie Barnett, Sydney Brenner, and Richard Watts-Tobin (23)
showed that the genetic code is a triplet code, the triplets do not overlap, the code contains no com-
mas, and each gene sequence is read from a specific starting point. Independently, Marshall Niren-
berg and Heinrich Matthaei showed that ribosomes translated poly-U into poly-phenylalanine
(62). Within a very short time, the Nirenberg group, as well as Gobind Khorana’s group, deter-
mined virtually all of the genetic code (46, 61). Concurrently, insights gained from genetic exper-
iments suggested to Brenner, François Jacob, and Meselson the existence of and ways to identify
mRNA (11). They were not alone in discovering mRNA; several other groups working indepen-
dently arrived at similar results through completely different routes (19). In addition, three groups
working independently purified and characterized the DNA-dependent RNA polymerase (43).
The advances made on the subject of regulation of gene activity crowned all of the other
achievements published in 1961. While many systems were investigated, there is little doubt that
the most influential work on the subject came from François Jacob and Jacques Monod. By apply-
ing genetic analyses to study the induction of β-galactosidase activity in E. coli, they opened up a
whole new world of how genes are turned off and on (65). In particular, by 1961, they published
their landmark paper presenting their accumulated genetic evidence on how the lactose-utilization
8 Kolter
genes were regulated in E. coli (45). Therein, they proposed their operon model, wherein multiple
genes encoding enzymes were regulated by a repressor gene acting on an operator gene. Their
ideas proved to have a long-lasting and extremely strong influence on how molecular biologists
approached the studies of gene regulation.
Fittingly, Jacob and Monod were asked to write the closing comments on the collection of pa-
pers compiled in the 1961 volume of the Cold Spring Harbor Symposium on Quantitative Biology (60).
A quick look at the table of contents of that volume makes it clear why 1961 can be designated as
an annus mirabilis for molecular biology (89). Still, Jacob and Monod’s work stood out as particu-
larly special. In their closing comments, when addressing the possibility of the universality of the
mechanisms of gene expression and its regulation, they wrote a phrase that is often attributed to
Monod: “anything found to be true of E. coli must also be true of Elephants” (60, p. 393). While
they do not cite him, this was definitely an elaboration on Kluyver’s statement on the unity of
biochemistry. Now, Jacob and Monod proclaimed the unity of molecular genetics.
Throughout the following 60 years, to the present day, focused studies on model organisms
have led to remarkable advances in our understanding of the molecular biology of bacteria. These
successes with model organisms helped attract many who were studying bacterial pathogens to
take on molecular genetic approaches. Greatly due to the influence of the studies of Stanley Falkow
and many of his trainees, microbial pathogenicity is now largely viewed through the lens of molec-
ular biology to understand the roles that virulence factors play in infection and disease (29, 30).
Thus were medical and molecular microbiology unified.
The wealth of new molecular knowledge is most certainly awe inspiring. Yet, standing alone,
these approaches can easily lead one to lose sight of three critical and inseparable aspects of all of
life: the metabolism that maintains the living state, the ecological context in which an organism
lives, and how evolution plays out in that context. It is very easy, in the midst of enthusiastically
pursuing molecular mechanistic studies, to lose sight of the concepts so beautifully summarized
in the titles of three important writings seldom read by molecular biologists: Bacterial Metabolism
(1969), by Horst W. Doelle (25), The Ecological Theater and the Evolutionary Play (1965), by G.
Evelyn Hutchinson (44), and “Nothing in Biology Makes Sense Except in the Light of Evolution”
(1973), by Theodosius Dobzhansky (24).
BACK FROM THE ASHES, MICROBIAL ECOLOGY RISES AGAIN

At the time that work on E. coli garnered more and more attention for its contributions to molec-
ular biology, those interested in the broader question of the evolutionary relationships among
microbes were in a state of crisis. From Kluyver’s work, two important principles emerged: not
only the unity of biochemistry but also the concept of comparative biochemistry, which led to the
unraveling of the metabolic pathways underlying much of microbial life (48). That had led him
and Van Niel, in 1936, down the path of establishing a “natural system of classification” of bacteria,
that is, one that reflected their evolutionary relatedness, their phylogenies (49). But by the 1950s,
frustrated by the seeming impossibility of establishing evolutionary relationships for bacteria,
Van Niel disavowed it and stated that, in his opinion, such attempts were a waste of time (69). In
its stead, Stanier and Van Niel (72) proposed—in their landmark 1962 paper, “The Concept of a
Bacterium”—the prokaryote-eukaryote distinction. While it was based on cellular organization,
it quickly was adopted as a phylogenetic distinction (69). Prokaryota (or Monera) was a kingdom
defined by the lack of a nuclear membrane, chromosomes, mitosis, meiosis, mitochondria, etc.,
as if these traits would evolve later along a single time line. It should not surprise us that for
those steeped in molecular biology in the 1960s and early 1970s there could “be little doubt that
the simpler prokaryotes are the evolutionary antecedents of the more complex eukaryotes,” as

Gunther Stent wrote in his 1971 text Molecular Genetics (73, p. 43). Evolutionarily, present-day
prokaryotes were seen as living fossils, the primitive precursors of protists, fungi, plants, and
animals. Evolution was seen as going from less complex and less diverse prokaryotes to the
much more complex and diverse eukaryotes. Importantly, the prokaryote-eukaryote dichotomy
offered no path to quantitate the evolutionary relatedness between organisms. But a powerful
new approach to determine such relationships was already emerging, sequence comparisons.
The idea of using sequence comparisons to establish phylogenies was around before there were
sequences to compare. In 1958, Crick presciently alluded to how comparing protein sequences
would reveal “vast amounts of evolutionary information” (22, p. 142). Within a decade, molecular
evolution got its start by comparing sequences of cytochromes (54) and hemoglobin (95) to derive
phylogenies. Realizing the power of this approach, Stanier changed his perspective and saw the
possibility of using it to establish a bacterial phylogeny (69). However, it would not be Stanier but
a relative outsider who would first establish a molecular phylogeny of bacteria and, in so doing,
turn the prevalent worldview of the natural history of life on Earth on its head and establish a
universal phylogeny.
Carl Woese was one of the many physical scientists who became deeply immersed in studying
protein synthesis in the early 1960s. Unlike many of his contemporary colleagues, he was primar-
ily interested in the evolution of translation and the genetic code. His approach was to arrive at
a molecular phylogeny of the translation machinery by comparing sequences of a component of
the ribosome. Recall, however, that at the time there were no sequences for ribosomal proteins
or RNAs. He brilliantly chose to compare sequences of the small ribosomal subunit RNA (16S
rRNA in bacteria) to arrive at phylogenetic distances. There was no DNA sequencing at the time,
and RNA sequencing was an arduous task. Taking on the job of obtaining sequence information
for numerous rRNA molecules of 1,500 bases was a Herculean effort. In fact, the determination
of the complete 16S rRNA sequence was not achievable at the time; only catalogs of oligonu-
cleotides of known sequence could be obtained and then compared. Despite all the difficulties, by
the mid-1970s Woese and colleagues (91) obtained and compared oligonucleotide catalogs from
more than two dozen rRNAs. The results proved to be earth-shattering. In their landmark 1977
paper, Woese and George Fox (90) reached the conclusion that methanogens, long believed to be
bacteria, were as different from bacteria as they were from eukaryotes. Some immediately recog-
nized the significance of the results, but others, particularly molecular biologists and evolutionary
biologists, did not (69). Woese and Goldenfeld (92) make this evident in their essay recollect-
ing the entire process, “How the Microbial World Saved Evolution from the Scylla of Molecular
Biology and the Charybdis of the Modern Synthesis.”
Woese and colleagues continued their efforts with newfound determination over the next
13 years. Improvements in sequencing and gene isolation greatly accelerated the process of se-
quence gathering and comparisons. In a 1990 paper with Otto Kandler and Mark Wheelis, Woese
presented the universal phylogenetic tree, with three domains: Bacteria, Archaea, and Eukarya
(93). While it took some years for this new worldview to sink in across all of biology, its im-
plications for our understanding of the evolutionary process were monumental. The universal
phylogeny lent strong support to a common origin of all life and confirmed Lynn Margulis’s en-
dosymbiont hypothesis (63). The evolution of members of all three domains of life continued;
no longer were prokaryotes viewed as evolutionary antecedents of eukaryotes. And, of particular
interest for microbial ecology, the vast majority of the sequence diversity on Earth was in the
microbial world.
The universal tree of life beckoned microbiologists to come explore its mysteries. Soon, there
was an added incentive that made that exploration even more attractive. Vigdis Torsvik, Jostein
Goksøyr, and Frida Daae took an approach to assess microbial diversity that was radically different
10 Kolter
from what had been done before. Rather than cultivating bacteria present in soil, they extracted
the DNA and assessed its complexity. Their results were astounding. The soil DNA they analyzed
contained at least 4,000 different genomes per gram of soil (78), a previously unimagined diversity.
The technique Torsvik and colleagues used, cot analysis, relied on reannealing kinetics of dena-
tured DNA and was developed in the 1960s by Roy Britten and David Kohne to analyze repeated
sequences in eukaryotic genomes (12). One has to wonder why it took more than 20 years for
someone to consider analyzing the complexity of environmental DNA directly, instead of assessing
diversity only through cultivation. The question is very relevant because for decades investigators
had noted the “great plate count anomaly” (71, p. 327), the orders-of-magnitude difference be-
tween the numbers of cells observed through the microscope and the numbers of colony-forming
units in environmental samples. The lack of communication across disciplines certainly had to
play a role in this decades-long delay.

Norman Pace and his colleagues were among the first of a new breed of intrepid explorers.
They chose Yellowstone National Park as the site for their explorations. They used PCR to amplify
small-subunit rRNA gene sequences from DNA extracted directly from hot spring sediment. They
then cloned the products and sequenced them. Remarkably, in a single hot spring they found more
archaeal diversity than had been found in all the previously cultivated archaea (5).
Once environmental microbiologists became aware of the riches waiting to be discovered
through culture-independent approaches, there was a massive rush to explore every corner of
the biosphere. The new approach generated great enthusiasm even among those previously not
involved in microbiology. Witness the closing words of Edward O. Wilson (88, p. 364), preemi-
nent ant ecologist, in his autobiography, Naturalist: “If I could do it all over again, and relive my
vision in the twenty-first century, I would be a microbial ecologist. Ten billion bacteria live in a
gram of ordinary soil, a mere pinch held between thumb and forefinger. They represent thousands
of species, almost none of which are known to science. Into that world I would go with the aid of
modern microscopy and molecular analysis. I would cut my way through clonal forests sprawled
across grains of sand, travel in an imagined submarine through drops of water proportionately the
size of lakes, and track predators and prey in order to discover new life ways and alien food webs.”
By 1997, when Pace published his landmark review “A Molecular View of Microbial Diversity
and the Biosphere,” the culture-independent exploration of the planet was in full force, yielding
novel insights regarding the roles of microbes in myriad environments (63). However, one
environment remained largely unexplored, the human body. Except for a few limited studies, the
human body was not surveyed by culture-independent methods during the 1990s. Twenty years
after Woese discovered Archaea and nearly ten years after the inception of culture-independent
molecular phylogenetic approaches, the schism between medical and environmental microbiology
remained as strong as ever.
REUNIFICATION: IT’S ALL ENVIRONMENTAL MICROBIOLOGY

Where were all those investigators interested in studying the human host and its interactions
with microbes during the last twenty years of the twentieth century? Were they not reading the
papers from the budding field of microbiomes? Maybe, maybe not. No doubt, the very successful
approach of studying host-pathogen interactions with model systems and pure cultures kept
many of them focused on their ongoing research. One of the earliest reports describing the high
diversity of the human gut microbiota using culture-independent methods was published in 1999
(75). Perhaps because its senior author, Joel Doré, had trained as an environmental microbiologist,
this pioneering work went relatively unnoticed for several years. All of this changed—surprisingly
late, but change it did. Better late than never.

Fifteen years after Torsvik described high bacterial diversity in soil, a widely read paper describ-
ing high microbial diversity in the human gut by Paul Eckburg, David Relman, and colleagues
appeared, in 2005 (28). The work was an eye-opener to many, and it triggered an explosion of re-
search on the human microbiota. Soon several laboratories that had been either working on model
microbes in pure culture or using them in animal models shifted to work on different aspects of
the human microbiota, using culture-independent approaches. This shift coincided with dramatic
improvements in sequencing methodologies and increases in computational capacity. The topic
gathered much interest from scientists and the public in general such that in 2007 the US National
Institutes of Health started the US$170-million, ten-year-long Human Microbiome Project (79).
The pendulum swung completely, and much has been learned in the process. Despite the abun-
dance of hyperbole and widespread inappropriate interpretations of causality (36), there is a lot
of wonderful work linking particular microbial community composition to functionality (7, 9). A
radical departure from the Kochian view of microbes, this new work fully embraces ecology.
This increased interest in understanding the interactions between humans and their associated
microbial communities has had a profound, and certainly very positive, impact in microbiology
as whole. Ecologists, evolutionary biologists, chemists, physicists, computational biologists, and
others have come into the field as their expertise has become essential. There is now a renewed
excitement around the study of microbes and their vast diversity of metabolic pathways with the
recognition that all ecosystems have microbes at their most foundational level. Ecological and
evolutionary principles now guide the study of microbes. Whether one is studying the human gut
or frozen lakes in Antarctica, it is all environmental microbiology.
There have been so many exciting new developments in this unified New Microbiology during
the last 15 years that it is impossible to present them all here. Recent history is still in the making,
and it is the most difficult to assess; others will cover those developments much better than I. I’ve
chosen to close this retrospective with brief mentions of three events that I think provide a guide
to the future of this unified microbiology and that have stimulated me greatly.
First, Laura Hug, Christopher Brown, Jillian Banfield, and collaborators provided us with a
new view of the tree of life (13, 42). They discovered the Candidate Phyla Radiation, 15% of the
domain Bacteria with precious few cultured representatives. That there is so much out there that
we still don’t know much about is both mind-boggling and utterly exciting: “If I could do it all
over again. . . I would be a microbial ecologist.” (88, p. 364).
Second, in 2014 Martin Blaser published Missing Microbes: How the Overuse of Antibiotics Is
Fueling Our Modern Plagues (8). As we get nearer the possibility of entering a post-antibiotic era and
we continue to produce obscenely huge quantities of antibiotics, Blaser brings forth an ecological
perspective not so much on the problem of resistance but on the pervasive damage that producing
and abusing antibiotics is having on human health. It is inspiring to have witnessed the dramatic
change in the author. As someone who for decades contributed beautifully to our understanding
of pathogens, he grew seamlessly into an avid defender of microbial diversity.
In a similar vein, the influence that Margaret McFall-Ngai is having on microbiology is awe-
inspiring (84). McFall-Ngai points out that she was trained as an animal physiologist. From that
perspective, she has explored the Vibrio-squid symbiosis with Ned Ruby (55). That system, how-
ever, has served as a beginning of very broad vistas, and for at least the last 15 years, she has
elaborated on her views on the unity of biology, where all animal (and I would add all plant) life
occurs in a microbially dominant Earth (56). As a consequence, McFall-Ngai is pushing for what
I consider is the key aspect of the future of education in the life sciences, a curriculum based on
the ecology and evolution of the biosphere that integrates microbiology and macrobiology into a
unified systems biology (41).
It is all biology!
12 Kolter
EPILOGUE
Doubtless some readers will find the foregoing historical narrative deficient in that it neglects
countless discoveries of importance to microbiology. Yes, I admit to such lacunae. But I suggest
we all need to gain some perspective on which events lead to major changes in thinking. For that
I found the words from Matt Meselson, paraphrased from his conversation with Frank Stahl, a
most useful guide: “The way I think of it is that there is a river, which is a period of time when
there are fundamental questions to be solved. . . . When these problems are solved, there are lots
of little rivulets. The river divides into thousands of branches, using these fundamental insights
into how life works and applying them to specific questions” (57). I have described what I see
as rivers, not rivulets.
DISCLOSURE STATEMENT
The author is not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
I am deeply indebted to Mechas Zambrano for our extensive discussions on the subject (usually
during our evening forest walks with the dogs) and her critical reading of the manuscript.
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tures and functions of soil microbial communities mediated by chemistry. mBio 9(4):e01175-18

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Annual Review of
Microbiology
Volume 75, 2021 Contents
The History of Microbiology—A Personal Interpretation

Roberto Kolter p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Similarities and Dissimilarities of COVID-19 and Other

Coronavirus Diseases
To Sing Fung and Ding Xiang Liu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p19
Culturing Human Gut Microbiomes in the Laboratory

Simone Renwick, Caroline M. Ganobis, Riley A. Elder, Connor Gianetto-Hill,
Gregory Higgins, Avery V. Robinson, Sarah J. Vancuren, Jacob Wilde,
and Emma Allen-Vercoe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49
Regulation of Bacterial Ribonucleases
Murray P. Deutscher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p71
Plasmodium vivax Latent Liver Stage Infection and Relapse: Biological
Insights and New Experimental Tools
Carola Schäfer, Gigliola Zanghi, Ashley M. Vaughan, and Stefan H.I. Kappe p p p p p p p p p p p p87
Cell-to-Cell Heterogeneity in Trypanosomes
Vanessa Luzak, Lara López-Escobar, T. Nicolai Siegel, and Luisa M. Figueiredo p p p p p p p p 107
Beyond Restriction Modification: Epigenomic Roles of DNA
Methylation in Prokaryotes
Brian P. Anton and Richard J. Roberts p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 129
Cell Wall Biology of Vibrio cholerae
Laura Alvarez, Sara B. Hernandez, and Felipe Cava p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 151
Antimicrobial Activity of Metals and Metalloids
Yuan Ping Li, Ibtissem Ben Fekih, Ernest Chi Fru, Aurelio Moraleda-Munoz,
Xuanji Li, Barry P. Rosen, Masafumi Yoshinaga, and Christopher Rensing p p p p p p p p p p 175
Genome-Scale Metabolic Modeling of the Human Microbiome in the
Era of Personalized Medicine
Almut Heinken, Arianna Basile, Johannes Hertel, Cyrille Thinnes, and Ines Thiele p p p p 199
Causative Microbes in Host-Microbiome Interactions
Graham J. Britton and Jeremiah J. Faith p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 223
Quantitative Control for Stoichiometric Protein Synthesis
James C. Taggart, Jean-Benoît Lalanne, and Gene-Wei Li p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 243
vi
Bacterial Multicellularity: The Biology of Escherichia coli Building

Large-Scale Biofilm Communities
Diego O. Serra and Regine Hengge p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 269
Transcriptional Pausing as a Mediator of Bacterial Gene Regulation
Robert Landick p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 291
Growth and Division of the Peptidoglycan Matrix
Patricia D.A. Rohs and Thomas G. Bernhardt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 315
Evolution and Physiology of Amphibious Yeasts
Fouad El Baidouri, Polona Zalar, Timothy Y. James, Amy S. Gladfelter,
and Anthony S. Amend p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 337

Expanding Archaeal Diversity and Phylogeny: Past, Present, and
Future
Guillaume Tahon, Patricia Geesink, and Thijs J.G. Ettema p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 359
Two P or Not Two P: Understanding Regulation by the Bacterial
Second Messengers (p)ppGpp
Gert Bange, Ditlev E. Brodersen, Anastasia Liuzzi, and Wieland Steinchen p p p p p p p p p p p p 383
Imaging Infection Across Scales of Size: From Whole Animals to
Single Molecules
Eric P. Skaar p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 407
Microbial Rhodopsins: The Last Two Decades
Andrey Rozenberg, Keiichi Inoue, Hideki Kandori, and Oded Béjà p p p p p p p p p p p p p p p p p p p p p p p 427
Quorum Sensing in Fungal Species
Xiuyun Tian, Hao Ding, Weixin Ke, and Linqi Wang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 449
The Type VII Secretion System in Staphylococcus
Lisa Bowman and Tracy Palmer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 471
Trypanosome Signaling—Quorum Sensing
Keith R. Matthews p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 495
Hostile Takeover: How Viruses Reprogram Prokaryotic Metabolism
Tyler B. Jacobson, Melanie M. Callaghan, and Daniel Amador-Noguez p p p p p p p p p p p p p p p p p 515
Multiscale Dynamic Structuring of Bacterial Chromosomes
Virginia S. Lioy, Ivan Junier, and Frédéric Boccard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 541
Molecular Basis of Lysis–Lysogeny Decisions in Gram-Positive Phages
Aisling Brady, Alonso Felipe-Ruiz, Francisca Gallego del Sol, Alberto Marina,
Nuria Quiles-Puchalt, and José R. Penadés p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 563
Deciphering the Chitin Code in Plant Symbiosis, Defense, and
Microbial Networks
Devanshi Khokhani, Cristobal Carrera Carriel, Shivangi Vayla, Thomas B. Irving,
Christina Stonoha-Arther, Nancy P. Keller, and Jean-Michel Ané p p p p p p p p p p p p p p p p p p p p 583
Contents vii
Bacterial Outer Membrane Vesicles: From Discovery to Applications

Mariana G. Sartorio, Evan J. Pardue, Mario F. Feldman,
and M. Florencia Haurat p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 609
Origin and Early Evolution of the Eukaryotic Cell
Toni Gabaldón p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 631
Cellular Adaptations to Cytoplasmic Mg2+ Limitation
Eduardo A. Groisman and Carissa Chan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 649
Virulence and Pathogenicity of Chytrid Fungi Causing Amphibian
Extinctions
Matthew C. Fisher, Frank Pasmans, and An Martel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 673

Life in the Dark: Phylogenetic and Physiological Diversity of
Chemosynthetic Symbioses
E. Maggie Sogin, Manuel Kleiner, Christian Borowski,
Harald R. Gruber-Vodicka, and Nicole Dubilier p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 695
The Bacterial Hsp90 Chaperone: Cellular Functions and Mechanism
of Action
Sue Wickner, Thu-Lan Lily Nguyen, and Olivier Genest p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 719
Indexes
Cumulative Index of Contributing Authors, Volumes 71–75 p p p p p p p p p p p p p p p p p p p p p p p p p p p 741
Errata
An online log of corrections to Annual Review of Microbiology articles may be found at

http://www.annualreviews.org/errata/micro
viii Contents
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From the Annual Review of Animal Biosciences, Volume 9 (2021)

Advances in Microbiome Research for Animal Health
Raquel S. Peixoto, Derek M. Harkins, and Karen E. Nelson

Bacteriome Structure, Function, and Probiotics in Fish Larviculture: The Good,
the Bad, and the Gaps
Nuno Borges, Tina Keller-Costa, Gracinda M.M. Sanches-Fernandes,
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Designing Biological Circuits: Synthetic Biology Within the Operon Model and
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Preparing Better Samples for Cryo–Electron Microscropy:
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Benjamin C. McIlwain, Michal T. Ruprecht, and Randy B. Stockbridge
A Natural Product Chemist’s Guide to Unlocking Silent Biosynthetic
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ix
From the Annual Review of Genetics, Volume 54 (2020)

Molecular Mechanisms of CRISPR-Cas Immunity in Bacteria
Philip M. Nussenzweig and Luciano A. Marraffini
Toxin-Antidote Elements Across the Tree of Life
Alejandro Burga, Eyal Ben-David, and Leonid Kruglyak
Genetic Diversity in Mycobacterium tuberculosis Clinical Isolates and Resulting
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Brittany M. Miller and Andreas J. Bäumler
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Eduard Ansaldo, Taylor K. Farley, and Yasmine Belkaid
The Innate Immune Response to Mycobacterium tuberculosis Infection
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Related Articles xi

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Annu. Rev. Microbiol. 2021.75:1-17. Downloaded from www.annualreviews.

Annu. Rev. Microbiol. 2021. 75:1–17 Keywords

The Annual Review of Microbiology is online at Abstract

REUNIFICATION: IT’S ALL ENVIRONMENTAL MICROBIOLOGY . . . . . . . . . . 11

MICROBIOLOGY COMES OF AGE

THE FIRST SCHISM—THE BIRTH OF MEDICAL MICROBIOLOGY

www.annualreviews.org • The History of Microbiology 3

interested in microbial ecology.

THE SECOND SCHISM—THE BIRTH OF MOLECULAR BIOLOGY

WHERE ART THOU, GENERAL MICROBIOLOGY?

www.annualreviews.org • The History of Microbiology 5

THE GOLDEN AGE (AND THE DARK SIDE) OF ANTIBIOTICS

www.annualreviews.org • The History of Microbiology 7

BACK FROM THE ASHES, MICROBIAL ECOLOGY RISES AGAIN

www.annualreviews.org • The History of Microbiology 9

play a role in this decades-long delay.

REUNIFICATION: IT’S ALL ENVIRONMENTAL MICROBIOLOGY

www.annualreviews.org • The History of Microbiology 11

be perceived as affecting the objectivity of this review.

www.annualreviews.org • The History of Microbiology 13

figure out the details of

great justice to the work

www.annualreviews.org • The History of Microbiology 15

www.annualreviews.org • The History of Microbiology 17

Volume 75, 2021 Contents

The History of Microbiology—A Personal Interpretation

Similarities and Dissimilarities of COVID-19 and Other

Culturing Human Gut Microbiomes in the Laboratory

Bacterial Multicellularity: The Biology of Escherichia coli Building

and Anthony S. Amend p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 337

Bacterial Outer Membrane Vesicles: From Discovery to Applications

Matthew C. Fisher, Frank Pasmans, and An Martel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 673

Cumulative Index of Contributing Authors, Volumes 71–75 p p p p p p p p p p p p p p p p p p p p p p p p p p p 741

An online log of corrections to Annual Review of Microbiology articles may be found at

From the Annual Review of Animal Biosciences, Volume 9 (2021)

Raquel S. Peixoto, Derek M. Harkins, and Karen E. Nelson

From the Annual Review of Biochemistry, Volume 90 (2021)

From the Annual Review of Genetics, Volume 54 (2020)

From the Annual Review of Immunology, Volume 39 (2021)

The Habitat Filters of Microbiota-Nourishing Immunity

From the Annual Review of Medicine, Volume 72 (2021)

From the Annual Review of Phytopathology, Volume 58 (2020)

From the Annual Review of Virology, Volume 7 (2020)

Cellular Electron Cryo-Tomography to Study Virus-Host Interactions

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